Voltage-gated sodium channels are transmembrane proteins that mediate regenerative inward currents that are responsible for the initial depolarization of action potentials in excitable cells, such as neurons and muscle. Sodium channels are typically a complex of various subunits, the principle one being the alpha-subunit. The alpha-subunit is the pore-forming subunit, and it alone is sufficient for all known sodium channel function. However, in certain sodium channels, smaller, auxiliary subunits called beta-subunits are known to associate with the larger alpha-subunit and are believed to modulate some of the functions of the alpha-subunit. (See Kraner, et al. (1985) J Biol Chem 260:6341-6347; Tanaka, et al. (1983) J Biol Chem 258:7519-7526; Hartshorne, et al. (1984) J Biol Chem 259:1667-1675; Catterall, (1992) Physiol Rev 72:S14-S48; Anderson, et al. (1992) Physiol Rev 72:S89-S158.) A review of sodium channels is presented in Catterall, (1995) Ann Rev Biochem 64:493-531.
The primary structures of sodium channel alpha-subunits from a variety of tissues (brain, peripheral nerve, skeletal muscle, and cardiac muscle) and organisms (jellyfish, squid, eel, rat, human) have been identified, and their amino acid sequences show individual regions which have been conserved over a long evolutionary period (see Alberts, et al., eds., “Molecular Biology of the Cell” 534-535, Garland Pub., New York, N.Y. (1994)). From these studies it is known that the alpha-subunit of a sodium channel is a large glycoprotein containing four homologous domains (labeled I-IV in FIG. 1) connected by intracellular loops. The N-terminus of the alpha-subunit extends intracellularly at domain I (i.e., DI) and the C-terminus of the alpha-subunit extends intracellularly at domain IV (i.e., DIV). In the plasma membrane, the four domains orient in such a way as to create a central pore whose structural constituents determine the selectivity and conductance properties of the sodium channel.
Each domain of the sodium channel alpha-subunit contains six transmembrane alpha-helices or segments (labeled 1-6 in FIG. 1). Five of these transmembrane segments are hydrophobic, whereas one segment is positively charged with several lysine or arginine residues. This highly charged segment is the fourth transmembrane segment in each domain. Extracellular loops connect segment 1 (i.e., S1) to segment 2 (i.e., S2) and segment 3 (i.e., S3) to segment 4 (i.e., S4). Intracellular loops connect S2 to S3 and S4 to segment 5 (i.e., S5). An extracellular re-enterant loop connects S5 to segment 6 (i.e., S6). (See Agnew, et al. (1978) Proc Natl Acad Sci USA 75:2606-2610; Agnew, et al. (1980) Biochem Biophys Res Comm 92:860-866; Catterall, (1986) Ann Rev Biochem 55:953-985; Catterall, (1992) Physiol Rev 72:S14-S48.)
Voltage-gated sodium channels can be named according to a standardized form of nomenclature outlined in Goldin, et al. (2000) Neuron 28:365-368. According to that system, voltage-gated sodium channels are grouped into one family from which nine mammalian isoforms and have been identified and expressed. These nine isoforms are given the names Nav1.1 through Nav1.9. Also, splice variants of the various isoforms are distinguished by the use of lower case letters following the numbers (e.g., “Nav1.1a”).
Because of the important role sodium channels play in the transmission of action potentials in excitable cells like neurons and muscle, sodium channels have been implicated in many sensory, motor, and neurologic disorders. Accordingly, sodium channels have been the focus of much scientific research. However, while a great deal has been learned about sodium channels, there remains a need for further understanding of the functioning of sodium channels, and means to diagnose, predict, prevent, and treat diseases, disorders, and conditions that result from variations and abnormalities of sodium channels. These and other objects and advantages of the materials, compositions, articles, devices, and methods described herein, as well as additional inventive features, will be apparent from the following disclosure.